Pyridinium compounds are of interest in drug design or as general intermediates for organic syntheses, e.g., especially in natural product synthesis. (Cheng, W.-C. and Kurth, M. J., Organic Preparations and Procedures International 34 (2002) 585-608). The standard synthetic route in the production of substituted pyridinium compounds is via alkylation of pyridine derivatives. However, this reaction is only convenient when using primary alkyl halides. When secondary or tertiary alkyl halides are used, elimination occurs as an unwanted side reaction and yields are generally low. Moreover when the alkylation is performed with alkyl halides with the halogen atom attached to an asymmetric carbon atom, racemization can occur during the nucleophilic displacement reaction.
These limitations may be overcome by using the “Zincke reaction” which is based on the reaction of Zincke salts with alkyl or aryl amines. Zincke salts are activated pyridinium salts which are capable of reacting with a primary amine (R—NH2), wherein at the nitrogen in 2 or 6 position, respectively, ring opening is induced which in turn is followed by ring closing to an R-substituted pyridinium compound. The Zincke reaction can also be performed with hydrazines, hydroxyl amines and carboxylic acid hydrazides. These types of Zincke reactions are used for in solution and for solid phase organic syntheses (Eda, M. et al., J. Org. Chem. 65 (2000) 5131-5135). In the art the predominant way for preparing the desired Zincke salts is by reacting a pyridine derivative with 2,4 dinitro halobenzol, for example,with 2,4 dinitrochlorbenzol and 2,4 dinitrobrombenzol.
As obvious from the above description of state of the art processes, the presently used activation reagents are either toxic, explosive, or otherwise hazardous and therefore limited to small scale research applications. There are scattered attempts to perform the Zincke reaction in an eco-friendly manner, e.g., by using microwave assisted synthesis. However this attempt still relies on explosive dinitrophenyl compounds and it is not possible to scale up this method without taking expensive precautionary measures (Vianna, G. H. R. et al., Letters in Organic Chemistry 5 (2008) 396-398). Another major limitation of the Zincke method is the fact that electron-poor reactants like 3-acyl substituted pyridines hardly react with 2,4-dinitro halogenated benzenes to the corresponding Zincke salts (Genisson, Y. et al., Synlett. 5 (1992) 431-434).
It is known that various 2-alkylaminopentadienimin derivatives react with NH4OAc or primary amines (R—NH2) under acidic conditions to the corresponding 3-alkylated pyridines, respectively, 1-R-3-alkyl-substituted pyridinium compounds. The required 2-alkylaminopentadienimin compounds are accessible from N-tertbutylimino derivatives of aldehydes, deprotonated with LDA and reacted with vinamidinium chloride (Wypych, J. C. et al., J. Org. Chem. 73 (2008) 1169-1172).
However, the utility of this method is unfortunately limited. No reactive groups, such as acyl functions, can be introduced in position 2 of the aminopentadienimin system, what, for example, would be a prerequisite for the synthesis of 1-R-3-acyl-substituted pyridinium compounds.
Therefore there is quite a need to improve the synthesis of N-substituted Acyl pyridinium compounds, for example by avoiding hazardous activation reagents. Novel less critical methods should allow for more safe production procedures and for easier, less risky and more efficient production of such compounds at much larger scale.